title: p21 promotes sustained liver regeneration and hepatocarcinogenesis in chronic cholestatic liver injury.
abstract: OBJECTIVE
  The cyclin-dependent kinase inhibitor p21 has been implicated as a tumour suppressor. Moreover, recent genetic studies suggest that p21 might be a potential therapeutic target to improve regeneration in chronic diseases. The aim of this study was to delineate the role of p21 in chronic liver injury and to specify its role in hepatocarcinogenesis in a mouse model of chronic cholestatic liver injury.
  
  
  METHODS
  The degree of liver injury, regeneration and tumour formation was assessed in Mdr2(-/-) mice and compared with Mdr2/ p21(-/-) mice. Moreover, the role of p21 was evaluated in hepatoma cells in vitro and in human hepatocellular carcinoma (HCC).
  
  
  RESULTS
  Mdr2(-/-) mice developed HCCs as a consequence of chronic inflammatory liver injury. In contrast, tumour development was profoundly delayed in Mdr2/ p21(-/-) mice. Delayed tumour development was accompanied by markedly impaired liver regeneration in Mdr2/ p21(-/-) mice. Moreover, the regenerative capacity of the Mdr2/ p21(-/-) livers in response to partial hepatectomy declined with age in these mice. Hepatocyte transplantation experiments revealed that impaired liver regeneration was due to intrinsic factors within the cells and changes in the Mdr2/ p21(-/-) microenvironment. In human HCCs, a subset of tumours expressed p21, which was associated with a significant shorter patient survival.
  
  
  CONCLUSIONS
  We provide experimental evidence that p21 is required for sustained liver regeneration and tumour development in chronic liver injury indicating that p21 needs to be tightly regulated in order to balance liver regeneration and cancer risk. Moreover, we identify p21 as a negative prognostic marker in human HCC.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Marhenke
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Laura Elisa
authors.initials: LE
authors.lastname: Buitrago-Molina
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Endig
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Orlik
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Schweitzer
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Klett
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.affiliation: Genome Analytics Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: Departamento de Bioquímica y Biología Molecular II, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Aránzazu
authors.initials: A
authors.lastname: Sánchez Muñoz
authors.affiliation: Department of Genetics, Oregon Stem Cell Center, Oregon Health & Science University, Portland, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Dorrell
authors.affiliation: Department of Internal Medicine 1, Ulm University Hospital, Ulm, Germany.
authors.forename: Sarah-Fee
authors.initials: SF
authors.lastname: Katz
authors.affiliation: Department of Internal Medicine 1, Ulm University Hospital, Ulm, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Lechel
authors.affiliation: Department of Medicine II, Molecular Hepatology-Alcohol Associated Diseases, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Honglei
authors.initials: H
authors.lastname: Weng
authors.affiliation: Department of Pathology, Medical School Hannover, Hannover, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Krech
authors.affiliation: Department of Pathology, Medical School Hannover, Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lehmann
authors.affiliation: Department of Medicine II, Molecular Hepatology-Alcohol Associated Diseases, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors.forename: Karl Lenhard
authors.initials: KL
authors.lastname: Rudolph
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Vogel
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D002460:Cell Line; D002780:Cholestasis, Intrahepatic / Q000150:complications*; D002908:Chronic Disease; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006498:Hepatectomy; D048550:Hepatic Insufficiency / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology* / Q000601:surgery; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis
chemical_list: D015415:Biomarkers; D014408:Biomarkers, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21
keywords: CANCER; CELL CYCLE CONTROL; HEPATOCELLULAR CARCINOMA; LIVER